This invention relates generally to a method for carrying out an olefin metathesis reaction using a Group 8 transition metal complex as a catalyst. More particularly, the invention relates to a method for carrying out a ring-opening cross-metathesis (xe2x80x9cROCMxe2x80x9d) reaction using the aforementioned catalyst, in which a cycloolefin and a second olefinic reactant are selected with respect to their relative reactivity in the ROCM reaction. Methods are also provided for the catalysis of regioselective ROCM reactions and ROCM reactions involving at least one functionalized olefinic reactant.
The flexibility of the olefin metathesis reaction allows the efficient production of highly functionalized, unsaturated polymers and small molecules. Grubbs et al. (1998) Tetrahedron 54, 4413-4450; Randall et al. (1998) J. Mol. Cat. A-Chem. 133, 29-40; Trnka and Grubbs (2001) Acc. Chem. Res. 34, 18-29. Many synthetically relevant applications that involve more than one type of metathetical transformation utilize ruthenium catalysts such as (I) and molybdenum catalysts such as (II) 
wherein xe2x80x9cCyxe2x80x9d is a cycloalkyl group such as cyclohexyl or cyclopentyl. See Schwab et al. (1995) Angew. Chem., Int. Ed. Engl. 34, 2039-2041; Schwab et al. (1996) J. Am. Chem. Soc. 118, 100-110. Notably, the combination of ring-opening metathesis polymerization (ROMP) and cross-metathesis (CM) produces unique telechelic and multiple-block copolymers with novel properties. Chung et al. (1992) Macromolecules 25, 5137-5144; Hillmyer et al. (1997) Macromolecules 30, 718-721; Maughon et al. (2000) Macromolecules 33, 1929-1935; Morita et al. (2000) Macromolecules 33, 6621-6623; Bielawski et al. (2000) Angew. Chem. Int. Ed. Engl. 39:2903-2906. For a review on telechelic polymers, see E. J. Goethals, Telechelic Polymers: Synthesis and Applications, CRC, Boca Raton, Fla., 1989. The synthesis of substituted polyethers has also been achieved by the ring closing metathesis (RCM) of a short linear molecule followed by ROMP of this new monomer. Marsella et al. (1997) Angew. Chem. Int. Ed. Engl. 36, 1101-1103; Maynard et al. (1999) Macromolecules 32, 6917-6924. With regard to small molecules, ring opening-ring closing xe2x80x9ctandemxe2x80x9d sequences allow the rapid construction of mutiply fused ring systems, which include those in complex natural products. In each of these cases the product of one metathesis event is directly available for the next, which allows multiple metathesis routes to be synthetically exploited.
A variation on this theme that remains largely unexplored is ring-opening cross-metathesis (xe2x80x9cROCMxe2x80x9d), illustrated in the following scheme: 
ROCM actually involves a tandem sequence in which a cycloolefin is opened and a second, acyclic olefin is then crossed onto the newly formed termini. The wide synthetic availability of cycloolefins makes this route attractive, and cyclic compounds are particularly important in synthesis. Most significantly, ring systems are key to stereochemical control; the understanding of ring conformation often presents the most expeditious route for stereocenter installation. The ability to take these general carbocycles to highly functionalized linear molecules (which, ideally, would have differentially protected termini) would therefore be extremely valuable to the synthetic chemist.
Previous work in this area has focused on highly strained cyclobutene and norbornene derivatives, as illustrated in the following schemes: 
Randall et al. (1995) J. Am. Chem. Soc. 117:9610-9611; Snapper et al. (1997) J. Am. Chem. Soc. 119:1478-1479; Limanto et al. (2000) J. Am. Chem. Soc. 122:8071-8072; Schrader et al. (2000) Tetrahedron Lett. 41:9685-9689.
Both systems typically utilize steric congestion to disfavor ROMP relative to ROCM, which imposes stringent restrictions on the scaffolds open to this synthetic method. A more practical route would involve systems in which cross-metathesis can compete with polymerization, thereby directly limiting the size of the molecules produced. The invention is addressed, in part, to such a catalytic reaction, wherein the reactants as well as the catalyst are selected to maximize production of a monomeric or oligomeric product relative to the production of a telechelic polymer, via an ROCM route. The invention is also addressed to a method for producing monomers and oligomers that are xe2x80x9cend differentiatedxe2x80x9d rather than symmetrical, enhancing the selectivity and versatility of the ROCM reaction products in further synthetic processes.
Recently, significant interest has focused on the use of N-heterocyclic carbene ligands as superior alternatives to phosphines. See, e.g., Trnka and Grubbs, supra; Bourissou et al. (2000) Chem. Rev. 100:39-91; Scholl et al. (1999) Tet. Lett. 40:2247-2250; Scholl et al. (1999) Organic Lett. 1(6):953-956; and Huang et al. (1999) J. Am. Chem. Soc. 121:2674-2678. N-heterocyclic carbene ligands offer many advantages, including readily tunable steric bulk, vastly increased electron donor character, and compatibility with a variety of metal species. In addition, replacement of one of the phosphine ligands in these complexes significantly improves thermal stability. The vast majority of research on these carbene ligands has focused on their generation and isolation, a feat finally accomplished by Arduengo and coworkers within the last ten years (see, e.g., Arduengo et al. (1999) Acc. Chem. Res. 32:913-921). Representative of these second generation catalysts are the four ruthenium complexes (IVA), (IVB), (VA) and (VB): 
In the above structures, Cy is as defined previously, xe2x80x9cIMesxe2x80x9d represents 1,3-dimesityl-imidazol-2-ylidene 
and xe2x80x9cIMesH2xe2x80x9d represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene 
These transition metal carbene complexes, particularly those containing a ligand having the 4,5-dihydroimidazol-2-ylidene structure such as in IMesH2, have been found to address a number of previously unsolved problems in olefin metathesis reactions, and are the preferred catalysts for use in conjunction with the novel ROCM methodology.
The present invention is addressed to the aforementioned need in the art, and provides a novel process for carrying out selective ring opening cross metathesis of a cycloolefin, which may or may not be a strained cyclic structure. More specifically, the method involves a catalyzed ring-opening cross-metathesis (ROCM) reaction between a cyclic olefin and a second olefinic reactant, wherein the cyclic olefin is contacted with the second olefinic reactant in the presence of a Group 8 transition metal alkylidene catalyst under conditions and for a time period effective to allow the ROCM reaction to occur. The catalyst has the structure of formula (V) 
in which:
M is a Group 8 transition metal, particularly Ru or Os;
X1 and X2 may be the same or different, and are anionic ligands or polymers;
R1 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and carboxyl;
R2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl;
L is a neutral electron donor ligand; and
L1 is a neutral electron donor ligand having the structure of formula (VI) 
In structure (VI):
X and Y are heteroatoms selected from N, O, S, and P;
p is zero when X is O or S, and is 1 when X is N or P;
q is zero when Y is O or S, and is 1 when Y is N or P;
Q1, Q2, Q3, and Q4 are linkers, e.g., hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or xe2x80x94(CO)xe2x80x94;
w, x, y and z are independently zero or 1; and
R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl,
wherein any two or more of X1, X2, L, R1, R2, R3, R3A, R4, and R4A can be taken together to form a chelating multidentate ligand.
Accordingly, the complex of formula (V) may also be represented as (VII) 
In a preferred embodiment, L is an N-heterocyclic carbene having the structure of formula (VIII) 
wherein R3 and R4 are defined above, with preferably at least one of R3 and R4, and more preferably both R3 and R4, being alicyclic or aromatic of one to about five rings, and optionally containing one or more heteroatoms and/or substituents. Q is a linker, typically a hydrocarbylene linker, including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene linkers, wherein two or more substituents on adjacent atoms within Q may also be linked to form an additional cyclic structure, which may be similarly substituted to provide a fused polycyclic structure of two to about five cyclic groups. Q is often, although again not necessarily, a two-atom linkage or a three-atom linkage. Accordingly, the metal carbene complex of formula (VII) may also be represented as follows: 
It will be appreciated that a metathesis reaction between a cyclic olefin and a second olefinic reactant can result in several different types of reaction products, depending, in large part, on the relative rates of the ring-opening metathesis reaction and the cross-metathesis reaction between the second olefinic reactant and the cyclic olefin.
Accordingly, given that a cyclic olefin will undergo a ring opening reaction in the presence of the catalyst at a rate kRO, and that the second olefinic reactant will undergo a cross-metathesis reaction with the cycloolefin at a rate kCM, the invention in another embodiment involves selection of the two reactants such that the approximate relationship of kRO to kCM is already known, i.e., predetermined. See Morgan et al. (2002) Organic Letters 4(1):67-70, the disclosure of which is incorporated by reference. As will be explained in further detail infra, when kCM is greater than or equal to kRO, the ROCM product is predominantly a monomer, dimer, and/or oligomer, but not a polymer. More specifically, when kCM is approximately equal to kRO, the ROCM product is predominantly a dimer or oligomer, while when kCM is greater than kRO, the ROCM product is predominantly a monomer. Dimers and oligomers are of particular interest because their internal olefin moieties may be further functionalized by metathesis or other transformations.
Monomers are of interest as well, however, particularly when they can be prepared so as to be end differentiated, i.e., asymmetric with regard to the two terminal olefinic groups resulting from the ROCM reaction. It will be appreciated that kRO will be higher for moderately and highly strained cycloolefins such as cyclooctadiene, but lower for low-strain olefins such as cyclopentene and cyclohexene. Accordingly, in another embodiment, the invention pertains to an ROCM reaction in which kCM is sufficiently greater than kRO, so as to result in a predominantly monomeric product.
The invention additionally pertains to methods for selectively synthesizing an end-differentiated olefinic product, as alluded to above. In this case, the choice of cyclic olefin is relevant, insofar as a 1,1,2-trisubstituted olefin will preferentially result in an asymmetrically terminated olefinic product. Alternatively, or in addition, end differentiation can be achieved in a two-step process wherein, initially, a first ROCM step is carried out as above, and a second step involves a simple cross metathesis reaction of an additional olefin with the ROCM product. In the latter step, the catalyst may or may not have the structure of formula (VII). Alternative catalysts for the second, cross-metathesis reaction include, for example, bisphosphine complexes, e.g., complexes having the structure of formula (V) wherein L and L1 are phosphines of the formula PR5R6R7, where R5, R6, and R7 are each independently aryl or C1-C10 alkyl, particularly primary alkyl, secondary alkyl or cycloalkyl (such as xe2x80x94P(cyclohexyl)3, xe2x80x94P(cyclopentyl)3, xe2x80x94P(isopropyl)3), xe2x80x94P(phenyl)3, xe2x80x94P(phenyl)2(alkyl) and xe2x80x94P(phenyl)(alkyl)2). Such end differentiated olefinic products, by virtue of their asymmetry, have enhanced utility with regard to subsequent synthetic processes.